The present invention generally relates to iontophoretic systems for delivering medicaments such as therapeutic drugs and medicines to patients transdermally, i.e., through the skin, and more specifically relates to a stable iontophoretic drug delivery device and a reservoir for use in the same. In addition, the present invention relates to a method for making a stable iontophoretic drug delivery device with long shelf life and the reservoir for use in such a device.
Transdermal drug delivery systems have, in recent years, become an increasingly important means of administering drugs. Such systems offer advantages clearly not achievable by other modes of administration such as avoiding introduction of the drug through the gastro-intestinal tract or punctures in the skin to name a few.
Presently, there are two types of transdermal drug delivery systems, i.e., xe2x80x9cPassivexe2x80x9d and xe2x80x9cActive.xe2x80x9d Passive systems deliver drug through the skin of the user unaided, an example of which would involve the application of a topical anesthetic to provide localized relief, as disclosed in U.S. Pat. No. 3,814,095 (Lubens). Active systems on the other hand deliver drug through the skin of the user, such as a patient, using iontophoresis, which according to Stedman""s Medical Dictionary, is defined as xe2x80x9cthe introduction into the tissues, by means of an electric current, of the ions of a chosen medicament.xe2x80x9d
Conventional iontophoretic devices, such as those described in U.S. Pat. Nos. 4,820,263 (Spevak et al.), U.S. Pat. No. 4,927,408 (Haak et al.) and U.S. Pat. No. 5,084,008 (Phipps), the disclosures of which are hereby incorporated by reference, for delivering a drug or medicine transdermally through iontophoresis, basically consist of two electrodesxe2x80x94an anode and a cathode. Usually, electric current is driven from an external supply into the skin at the anode, and back out at the cathode. Accordingly, there has been considerable interest in iontophoresis to perform delivery of drugs for a variety of purposes. Two such examples, involve the use of Novocaine,(trademark) which is usually injected prior to dental work to relieve pain, and Lidocaine, which is usually applied as a topical, local anesthetic.
Such prior devices have prior hereto not been pre-loaded and self adhering, e.g., they have typically utilized an absorbent pad or porous solid sheet that can be filled with drug solution as the drug reservoir. These absorbent pads or porous sheets have three major disadvantages. First, they must be filled with the drug solution after removal from the package since these pads or porous sheets do not hold the drug solution as the solution is subject to removal and leakage under pressure or flexure. In addition, even after the inconvenient addition of the drug solution and after removal from the package, the absorbent pad or porous sheet reservoir remain subject to leakage and smearing of the drug solution due to pressure or flexure upon the skin. Furthermore, absorbent pads or porous solid sheets can not provide the electrical continuity to complete intimate contact since they lack adhesiveness and flexibility with the skin and its contours.
In addition, prior drug reservoirs have included pastes and unformed viscous semi-solid gels such as for example agar that have both solid and liquid characteristics as described, for example, in U.S. Pat. No. 4,383,529 (Webster), the disclosure of which is hereby incorporated by reference.
Powers et al., U.S. Pat. No. 4,886,277, although suggesting that Lidocaine could be incorporated into the reservoir, fails to solve the resulting problem associated with compatibility with adjacent materials such as conductive layers. Accordingly, such a device would fail to provide sufficient stability for extended shelf life, i.e., more than one year.
However, several disadvantages and limitations have been associated with the use of such devices, including handleability and loadability. For example, the semi-solid agar reservoir disclosed in Webster flows under shear or stress. Furthermore, this disclosed reservoir may melt upon exposure to modest elevated temperatures. The agar is unstable, spontaneously releasing aqueous solution.
Thus, there has been a need for an iontophoretic drug delivery device and a reservoir for use in the same, as well as a method for making the reservoir, which would eliminate the problems and limitations associated with the prior devices discussed above, most significant of the problems being associated with stability, handleability, loadability and electrocontinuity of the reservoir, including chemical and thermal stability of the reservoir and the electrode.
A reservoir electrode assembly of the present invention for an iontophoretic drug delivery device includes an electrode and a hydrophilic reservoir situated in electrically conductive relation to the electrode. The hydrophilic reservoir is formed from a bibulous hydrophilic cross-linked polymeric material having a first surface and a second surface that is adhesively adherent to the electrode. The first surface of the polymeric material is releasably adhesively adherent when applied to an area of a patient""s skin. The polymeric material has a cohesive strength forms an adhesive bond with a bond strength between the second surface of the polymeric material to the electrode that is greater than the cohesive strength of the polymeric material. Additionally, an adhesive bond strength of the first surface of the polymeric material to the applied area of the patient is less than the cohesive strength of the polymeric material so that upon removal of the reservoir assembly of the invention from the applied area of the patient, substantially no polymeric material remains on the applied area and the hydrophilic reservoir remains substantially intact and adhesively adherent to the electrode.
The reservoir electrode of the present invention provides solutions for several problems seen with available iontophoretic reservoir electrodes. The reservoir electrode of the invention, by being adherent to the skin of the patient minimizes current pathway concentrations that often result in irritation and burning caused by incomplete contact of the reservoir electrode assembly to the patient""s skin. Because the adhesive bond of the electrode to the patient""s skin is less than the cohesive strength of the polymeric material used for the reservoir, substantially no residue from the reservoir material is left behind on the patient""s skin. Additionally, since the polymeric reservoir material forms an adhesive bond with the electrode, there is intimate and effective electrical contact between the electrical circuit and the polymeric reservoir material. The reservoir electrode assembly of the invention can be physically smaller than most currently available electrode assemblies because the entire polymeric reservoir is hydrophilic and is utilized to contain drugs and electrolytes. Many current electrode assemblies require hydrophobic polymeric materials to achieve an adhesive tack and another hydrophilic material to retain the aqueous drug and electrolyte used for the iontophoretic delivery. When a hydrophobic and a hydrophilic component are used to form a reservoir, as in the currently available materials, some partitioning of the medicament may occur or there may be some binding of the active compound with the hydrophobic material that reduces the availability of the medicament for delivery. These effects are not seen with the hydrophilic reservoir of the invention.
In contrast to the prior devices discussed above, it has been found that a iontophoretic drug delivery device particularly suited for use to deliver at least one medicament, particularly in a high dose efficiency, can be constructed in accordance with the present invention by the incorporation of an aqueous swollen cross linked water soluble polymeric drug delivery reservoir adhesively coupled to the electrode such that the adhesive strength of the electrode material is greater than the cohesive strength of the reservoir material. In addition, the device of the present invention can easily fit over any contour of the body and provide excellent electrocoupling with the electrode and the skin, while still being capable of flexing and adhering to the skin. Also the device of the present invention can be applied over a range of temperatures and is stable for over one year at controlled room temperature to provide a commercially advantageous shelf-life.
The iontophoretic drug delivery device of the present invention for delivering at least one medicament to an applied area of a patient, such as the skin, mucous membrane and the like, including electrode assembly means for driving a medication into the applied area of the patient to be absorbed by the body of the patient, the electrode include an electrode material, and a covalently cross linked hydrophilic reservoir situated in electrically conductive relation to the electrode assembly means, with the reservoir including an aqueous swollen cross linked water soluble polymer material having an adhesive strength to the electrode material, an adhesive strength to the applied area and a cohesive strength to itself, with the reservoir containing at least one medicament, wherein the adhesive strength of the polymer material to the electrode material is greater than the cohesive strength of the polymer material and the adhesive strength of the polymer material to the applied area is less than the cohesive strength of the polymer material so that upon removal of the device from the applied area little if any polymer material remains on the applied area, while maintaining the reservoir intact and in intimate contact with the electrode material.
In the preferred embodiment, the device of the invention further includes a structurally reinforcing member situated within the reservoir including the aqueous swollen cross linked water soluble polymer, with the structurally reinforcing member having an open area that is thin and of sufficient voidage so as not to impede the flow of ions. In addition, the structurally reinforcing member is a thermoplastic polymeric scrim and the aqueous swollen cross linked water soluble polymer is cross linkable by high energy irradiation with the scrim being wettable enough and with open area of greater than 40% to insure phase continuity though the scrim, along with sufficient adhesion to contribute strength to the aqueous cross linked polymeric reservoir. Also, the aqueous swollen cross linked water soluble polymer is selected from the group including polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and polyacrylamide. The at least one medicament includes Lidocaine and the reservoir also includes a vasoconstrictor, stabilizers and glycerin. Further, the reservoir further includes additives and conductive salts, with the additives selected from the group including glycerin, propylene glycol, polyethylene glycol and preservatives.
The reservoir of the present invention for use in an iontophoretic drug delivery device having an electrode assembly including an electrically conductive electrode material for delivering at least one medicament through an applied area of a patient, such as the skin, mucous membrane and the like, includes a layer of a aqueous swollen cross linked water soluble polymer material capable of having electrocontinuity with the electrode assembly, with the aqueous swollen cross linked water soluble polymer material having sufficient adhesive tack including the at least one medicament for delivery through an applied area of a patient, such as the skin, mucous membrane and the like, and the aqueous swollen cross linked water soluble polymer material having an adhesive strength to the electrode material greater than the cohesive strength of the polymer material, and the cohesive strength being greater than an adhesive strength to the applied area.
In the preferred embodiment, the reservoir also includes a structurally reinforcing member situated within the layer of aqueous swollen cross linked water soluble polymer material, with the structurally reinforcing member having approximately 40% porosity so as not to impede the flow of ions, with the structurally reinforcing member being a wettable, scrim of a aqueous insoluble thermoplastic polymeric material and the aqueous swollen cross linked water soluble polymer material is cross linked by high energy irradiation. Also, aqueous swollen cross linked water soluble polymer is selected from the group including polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyacrylamide and polyethylene glycol. In addition, the at least one medicament includes Lidocaine and the aqueous swollen cross linked water soluble polymer material includes a vasoconstrictor, stabilizers and glycerin. Further, the reservoir includes additives and conductive salts, with the additives selected from the group including glycerin, propylene glycol and polyethylene glycol and preservatives.
The method of making a reservoir for an iontophoretic drug delivery device of the present invention includes the steps of providing a structurally reinforcing member, coating the reinforcing member with a viscous water soluble polymer solution on both sides of the structurally reinforcing member such that the polymer solution penetrates the open area, wets the reinforcing member, and cross linking the layer by high energy irradiation, with the cross-linked layer of polymer having an adhesive strength to an electrode material greater than a cohesive strength of the polymer, and the cohesive strength being greater than an adhesive strength to an applied area.
In the preferred embodiment of the method, the step of coating includes the steps of applying a layer of the viscous solution to one side of the reinforcing member, applying a layer of the viscous solution to one side of a release liner and laminating the release liner and the reinforcing material together such that both surfaces of the reinforcing member are coated with the viscous solution. In addition, the viscous solution is applied to the reinforcing member and the release liner to a thickness of about Ca. 5 mil to 70 mil. The method also includes the step of applying final release liners to the remaining exposed viscous solution coated surfaces of the reinforcing member to form a laminate and cross linking the viscous solution. Also, the method includes the steps of replacing one of the final release liners with an electrode in flexible sheet form, and adding at least one medicament to the cross linked water soluble polymer, with the at least one medicament includes Lidocaine and the cross linked water soluble polymer includes a vasoconstrictor, stabilizers, glycerin and preservative. Further, the method includes the of cutting the laminate into a suitable shape and area and laminating it to a conductive metal for use in an iontophoretic drug delivery device.